The p53 tumor suppressor pathway is a complex network of signals that fluctuate to regulate cell proliferation and death. Mdm2 and Mdm4 are crucial inhibitors of p53 and are often present at high levels in tumors thus dampening p53 activity eliminating the need for p53 mutations. Mdm2 also has p53-independent functions that promote chromosomal instability. Biochemical data indicated that Mdm2 and Mdm4 also bind p73, a p53 related protein. We have identified physiologically important interactions of Mdm2 with p73 in vivo. Thus, our overarching hypothesis is that the oncogenic functions of the Mdm proteins are a combined effect of inhibiting p53 and p73 functions. Furthermore, because normal cells, unlike tumor cells, do not tolerate high levels of Mdm2, we also hypothesize that tumor-specific changes alter cell physiology to tolerate high Mdm2 levels. To test these hypotheses, we will decipher the intricate relationship between p73 and Mdm2 by studying the phenotype of Mdm2-/-p73-/- mice. In addition, we will cross tumor prone Mdm2 transgenic and SNP309 mice (with higher than normal Mdm2 levels) with p73 mice to examine effects of concomitant p73 loss on chromosomal aberrations and tumor phenotypes. In aim 2, we will determine the physiological relevance of the Mdm4/p73 interactions, and we will generate p73 heterozygous Mdm4 transgenic mice to examine the importance of this combination on a tumor phenotype. Lastly, we will identify factors that allow tumor (but not normal) cells to tolerate high Mdm2 levels using genetic screens.